PROJECT SUMMARY Swallowing difficulties are extremely common and result in a substantial reduction in the quality of life and increased morbidity and mortality related to malnutrition and complications related to regurgitation and aspiration. Unfortunately, our understanding regarding the pathophysiology of dysphagia and GERD has been hampered by focusing predominantly on circular muscle activity and ignoring the biomechanical properties of the esophageal wall that promote normal emptying. Our initial work explored the relationship between intrabolus pressure (IBP) and esophagogastric junction (EGJ) compliance as a metric for outflow resistance. This work highlighted the direct relationship between IBP and EGJ opening and was the foundation for the development of a new classification scheme for esophageal motor disorders, ?the Chicago Classification.? Despite this improved understanding focused on bolus transit dynamics, there are still significant unresolved issues centered on the lack of a true correlate for symptoms or a predictive model for adverse outcomes. Given these limitations, we have evolved our focus toward a more directed assessment of how wall distensibility and the response of the esophageal body to volumetric distention will alter normal bolus transit. We hypothesize that the mechanical properties of the esophageal wall will likely alter bolus transport by disturbing the normal low pressure state that is required for asymptomatic bolus transit through the esophagus. In order to test our hypothesis that wall mechanics are a major determinant of esophageal diseases, we have had to develop new approaches and new technology to directly measure mechanical wall state. Using impedance techniques combined with manometry, we are now capable of assessing IBP and diameter changes across a space-time continuum (4D-IM). This approach will allow us to study the mechanics of bolus transport beyond the isometric circular muscle contraction quantified by manometry and allow us to assess the ability of the esophagus to accommodate the propagating bolus via isotonic relaxation and passive distention and the ability of the esophagus to propel the bolus via passive recoil and auxotonic contraction. Additionally, we have also modified FLIP techniques to assess the response of the esophageal wall to volumetric distention using FLIP-panometry analysis. The response of the esophageal wall to bolus retention or reflux is one of the most important functions of the esophagus in preventing complications of aspiration, reflux injury, or symptoms related to bolus retention. We recently reported that the normal response to volumetric distention is associated with repetitive antegrade contractions (RACs) and that this response was altered in specific disease states. Our overarching goal will be to study well-defined patient populations before and after interventions targeting wall distensibility to determine whether abnormalities in distensibility and response to volumetric distention are important predictors of outcome. This work will build upon the previous success of the Chicago Classification by defining new biomechanical biomarkers of disease activity and new targets for therapeutic intervention.